synthesis of pyrimidine derivatives - bu · pdf filesynthesis of pyrimidine derivatives a)...

INTRODUCTION INTRODUCTION

1

CC

C

NC

NC

C

CN

C

N

CC

CN

C

NC

C

CN

C

N

CC

CN

C

NC

C

CN

C

NC

C

CN

C

N

(ii) (i) (iii) (iv)

(v) (vi) (vii)

SYNTHESIS OF PYRIMIDINE DERIVATIVES

A) Synthesis of pyrimidine nucleus:

Pyrimidines (1,3-diazines) and their fused analogues form a large group

of heterocyclic compounds which share in building of nucleic acids, DNA

and RNA. These compounds have given attention in the last period due to

their interesting biological activities and therapeutic applications.

In fact, there are seven types of pyrimidine ring closure (i-vii)

depending upon the nature of fragments that combine together to form the

pyrimidine nucleus (1)

. Also, pyrimidine derivatives can be synthesized by

ring transformation and ring expansion.


2

CHO

+

O

Urea

YbCl3 NH

NH

Ph

O

Ph

O

ArCHONaOH

O

Ar

NH

C

NH2H2N

.HCl

N N

Ar

NH22a-f

i) Synthesis of pyrimidine from C-C-C and N-C-N fragments:

This type is the most useful and widely used one for the construction

of a pyrimidine ring from non-heterocyclic precursors. It involves the

condensation of an amidine, urea, thiourea, guanidine or their derivatives

with 1,3-bifunctional three-carbon fragment.

Condensation of benzaldehyde, cyclopentanone and urea in the presence

of YbCl3 (Lewis acid) under free-solvent conditions yielded pyrimidine

derivative (1) (2)

.

α-Ionone was condensed with different aldehydes under phase transfer

conditions and the produced chalcones were refluxed with guanidine

hydrochloride in isopropanol in the presence of silver oxide to afford the

pyrimidine derivatives (2a-f) (3)

.

Ar

a 4-MeO-C6H4

b 3-MeO-C6H4

c 4-Cl-C6H4

d 4-F-C6H4

e 4-BnO-C6H4

f 4-NO2-C6H4

1


3

N

O

R

NH

CNH2N

H

.HCl

Sodium isopropoxide,

Isopropanol

N

N

N

NH (CH2)3

R

N

N

N

N

(CH2)3

3a-e

4a-e

CH3COCH2CO2Et

O

NH2H2N

Cu(OTf)2

CH3CN

NH

NH

Ph

H3C O

EtO

OCHO

5

The biologically active pyrimidine derivatives (4a-e) were produced by

the reaction of chalcones (3a-e) with guanidine derivative in isopropanol

and sodium isopropoxide (4)

.

High yield of 3,4-dihydropyrimidin-2(1H)-one derivative (5) was

obtained by the three-component condensation reaction of benzaldehyde,

ethyl acetoacetate and urea in acetonitrile and employing copper (II) triflate as

a reusable catalyst (5)

.

The pharmacologically active 6-methylenesubstituted-4-trichloromethyl-

2-methylsulfanylpyrimidines (7a-d) were achieved by refluxing the

halogenated enone (6) with S-methylisothiourea sulphate in methanol/water

(3:1 v/v) in the presence of hydrochloric acid followed by nucleophilic

substitution reactions (6)

.

R

a H

b 4-SMe

c 4-Me

d 4-Cl

e 4-OMe


4

O

Cl3C

OCH3

Br MeS

NH

NH2

.H2SO4

2

MeOH/H2O

HClN

N

CCl3

SMe

Br

HZ

N

N

CCl3

SMeZ

CHO

R

O

OEtNC

NH

C

NH2H2N

.HCl NaOH, EtOHN

N

CN

OHH2N

R

The reaction of aromatic aldehydes, ethyl cyanoacetate and guanidine

hydrochloride in alkaline ethanol under reflux afforded 2-amino-5-cyano-6-

hydroxy-4-arylpyrimidines (8a-g) (7)

.

Z

a SC6H5

b Morpholin-4-yl

c Piperidinyl

d N(CH2CH3)2

R

a H

b 3-NO2

c 2-Cl

d 4-OMe

e 3-Cl

f 4-OH

g 2-NO2

6

7a-d

8a-g


5

NH2

NH

HNN Ar

O

F3C CH3

OEt

EtOH

rt

N

N

CF3

H3C NH

N Ar

C C

MeS

MeS CN

C

O

OMe

CH3CONH2

NaH

O

CNH

H3CC

C

SMe

COOMe

CN

MeOH

HN

N

H3C

O

COOMe

SMe

Novel 2-(N'-benzylidenehydrazino)-4-trifluoromethylpyrimidines (11a-f)

were produced by the cyclocondensation reaction of N-guanidino-

benzylimines (9a-f) with enone (10) through stirring in ethanol at room

temperature (8)

.

ii) Synthesis of pyrimidine from C-C-C-N and C-N fragments:

Ketenethioacetal (12) was reacted with acetamide in the presence of

sodium hydride in a mixture of benzene and DMA to give (13), which

cyclized on refluxing in methanol to the pyrimidine derivative (14) (9)

.

Ar

a C6H4

b 2-HO-C6H4

c 4-Me-C6H4

d 4-Cl-C6H4

e 4-MeO-C6H4

f 4-NO2-C6H4

9a-f 10

11a-f

12 13

14


6

N

HNH3C O

Ph

O

NH2

H3C OEt

O

PhNCO

15

O

EtO OEt

O

CF3CNNa / ether

OEtO

EtOOCNH2

CF3

OEtO

EtOOCN

CF3

CF3CNCF3

H2N

- EtOH

N

N

CF3

CF3HO

EtOOC

HN

NH

CN

S

S

Ph

S

NCSPh

NC

SH2N

6-Methyl-3-phenyluracil (15) was obtained by the reaction of ethyl

β-aminocrotonate with phenylisocyanate (10)

.

The condensation reaction of diethyl malonate and two molecules of

trifluoroacetonitrile furnished ethyl 2,6-bis(trifluoromethyl)-4-hydroxy-

pyrimidine-5-carboxylate (16) (11)

.

3-Phenylthioacryloylisothiocyanate was reacted with 2-cyanothio-

acetamide and yielded 6-styryl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-

5-carbonitrile (17) (12)

.

16

17


7

NH2H3C

O

X

Ar C NCS

O

NH2

H3C

S

NHX

O

ArO

- H2O

NH3C

S

NHX

O

Ar

C N

MeS

MeS

CN

NC-CH2CSNH2

NH2X

NC

N NH

NH2

MeS

CN

S

N

N

SMe

X NH2

NC

21

20

iii) Synthesis of pyrimidine from C-C-N and C-N-C fragments:

Addition of enaminoketone or enaminoester to aroylisothiocyanate

provided the intermediate (18), which undergoes cyclodehydration in basic

medium to give the corresponding pyrimidine derivative (19a-d) (13-15)

.

Cycloaddition of chalcogen (20) with 2-cyanothioacetamide in sodium

ethoxide afforded pyrimidine derivative (21) (16)

, while cycloaddition of

the same compound with 3-aminoacrylonitrile derivatives in DMSO and

anhy. K2CO3 at room temperature yielded the derivatives (22a,b) (17)

.

X Ar

a OEt C6H5

b OEt 4-MeO-C6H4

c OEt 4-Cl-C6H4

d CH3 C6H5CH=CH

X

a Pyrrolidinyl

b Morpholin-4-yl

18

19a-d

22a,b


8

NH2

NH2

O C(OEt)2 or

CO2 / MeOHNH

NH

O

23

NH2H3C

HNH2

O

N N

CH3HO

R

Base

+ (RCO)2O

24a,b

H3C CH

C

C

O

O

NH2

NH2

MeCH(COOMe)2

N N

HO

Me

OH

MeCHCO2Me

25

iv) Synthesis of pyrimidine from N-C-C-C-N and C fragments:

1,3-Diaminopropane was reacted with diethyl carbonate (18)

or carbon

dioxide in methanol (19)

and yielded perhydropyrimidin-2-one (23).

2-Alkenyl-6-methyl-4-hydroxypyrimidines (24a,b) were produced by

the reaction of β-aminocrotonamide with α,β-unsaturated acid anhydride

followed by cyclization in basic medium (20)

.

The reaction of 2-methylmalonodiamide with an ester such as

2-methylmalonic ester afforded 4,6-dihydroxypyrimidine derivative (25) (21)

.

R

a CH2=CH

b CH3-CH=CH


9

H

H3C CH3

CH3

O

HO NH4OAc

MW

H

H3C CH3

CH3

HN

H2N

PhCHO

MW

H

H3C CH3

CH3

N

N

H

Ph

H

H3C CH3

CH3

N

N

Ph

B 27

26 A

(CH2)n

O

+N

H2N SCH3

CN

DBU

N

N SCH3

NH2

(CH2)n

28

Steroidal pyrimidine (27) was prepared through microwave-assisted

three-component reaction of 2-hydroxymethylene-3-ketocholestan (26),

benzaldehyde and ammonium acetate for 6 min. The mechanism involves the

formation of β-aminoketoimine intermediate (A), which condensed with

benzaldehyde led to diimine intermediate (B). Then the latter was cyclized

and auto-oxidized to the product (22)

.

v) Synthesis of pyrimidine from C-N-C-N and C-C fragments:

The reaction of cyclopentanone or cyclohexanone with 3-cyano-2-

methylisothiourea in the presence of DBU as base catalyst afforded

4-aminopyrimidine derivatives (28) (23)

.

n = 1 or 2


11

NH

NR1

Y

R2

R3

COR4

- HY

N

N

R1

R3

COR4

R2

30 29 31

NH

O

HOOC

NH2

N

NH

O

Ph

O

32

1,3-Diaza-1,3-butadienes (29) were reacted with electron-deficient

acetylenes (30) under mild conditions to provide pyrimidine derivatives

(31) (24)

.

vi) Synthesis of pyrimidine from C-C-C-N-C and N fragments:

N-phenyluracil (32) was prepared by the addition of aniline to

N-propynoylcarbamic acid (25)

.

1-Chloro-1,1-difluoro-4-phenylaminobut-3-en-2-one was reacted with

n-propylamine and formaldehyde in DMSO under mild conditions and the

corresponding pyrimidine derivative (33) was obtained (26)

.

R1 = Ph, EtO2C, (EtO)2CH, Cl3C

R2 = H, Me, Ph, 4-Me-C6H4

R3 = H, Me, Ph, MeO2C

R4 = H, OMe, OEt

Y = OR, SMe, NMe2


11

H

PhHN

H

O

CF2Cl

CH3CH2CH2NH2 2 HCHO

DMSO

N

N

Ph

CH2CH2CH3

CF2Cl

O

33

N

C

CH3H3C

O CH3

S

H2N NH2 2

MeOH

rt

N N

NHHN

S

H3C

H3C

CH3 H3C

CH3

CH3

S

34

4-Isothiocyanato-4-methyl-2-pentanone was reacted with benzidine in

methanol at room temperature with two to one molar ratio and yielded

bis(2-thioxopyrimidin-1-yl) biphenyl derivative (34) (27)

.


12

N

C

CH3

O H

S

N NHNH2

MeOH

RefluxN NH N

NH

S

CH3

HO

35

HNR

NH

O

S

Ph

EtONa

NR

NH

O

S

Ph

37 36

HN

Ph

CO2C2H5

ONH2

PCl5 / CHCl3N

NH

Ph

CO2C2H5

OO

38

Pyrimidine-2-thione derivative (35) was obtained by refluxing

2-hydrazinopyridine with 3-isothiocyanatobutanal in methanol (28)

.

vii) Synthesis of pyrimidine from N-C-C-C-N-C fragment:

N-propenoylthiourea derivatives (36) were cyclized in sodium ethoxide

to 2-thioxoperhydropyrimidin-4-ones (37) (29)

.

Oxidative cyclization of ethyl ester of benzoyl asparagine by using

phosphorus pentachloride in chloroform yielded ethyl 2-phenyl-6-

oxotetrahydropyrimidine-5-carboxylate (38) (30)

.


13

N

O CH3

O

NH

Ph

O(CH3)2NH

N

N CH3

O

NH

Ph

O

CH3

39

O

N

X

OH

HOH2NAr

MW

K-10 clay OH

N

X

OH

HOArHN

O

N

X

OH

HOArHN

- H2O

N

N

X

OH

HO

Ar

40

41a-f 41a-f

viii) Synthesis of pyrimidine by ring transformation and ring

expansion:

2-Benzoylamino-6-methyl-1,3-oxazin-4-one was transformed into

pyrimidine derivative (39) via the reaction with dimethylamine (31)

.

Solvent-free microwave irradiation of a mixture of 1,3-oxazin-2-ones

(thiones) (40) and aromatic amines in the presence of K-10 clay through

amine-driven dehydrative ring transformation result in formation of

pyrimidine derivatives (41a-f) (32)

.

X Ar

a O C6H5

b O 4-Cl-C6H4

c O 4-MeO-C6H4

d S C6H5

e S 4-Cl-C6H4

f S 4-MeO-C6H4


14

NH

R1

H

N

O

N

O

R2

OEt

H2

Pd / C

NH

R1

H

NH

O

NH

O

R2

OEt

- EtOH

NR1

HN

OH

NH

O

R2

42

43

The hydrogenation of 1,2,4-oxadiazole derivatives (42) lead to the

reductive cleavage of N-O bond followed by cyclization to give the

pyrimidine derivatives (43) (33)

.


15

HN

N

N

H2N SCH2CO2Et

+ CH3COCH2CH(OMe)2N

a / EtO

H

N

N

N

SCH2CO2Et

rt

NH3C

45

44

HN

N

N

H2N SBn

+ CH2(COOEt)2

CH3ONa

N

N

N

N

OH

HO

SBn

46

B) Synthesis of fused pyrimidines:

1. Synthesis of triazolopyrimidines:

1.1. From triazole derivatives:

The aminotriazole derivative (44) was cyclized with acetylacetaldehyde

dimethylacetal in Na / EtOH at room temperature to give ethyl 2-(5-methyl-

1,2,4-triazolo[1,5-a]pyrimidin-ylthio)acetate (45) (34)

.

2-Benzylthio-5,7-dihydroxy-1,2,4-triazolo[1,5-a]pyrimidine (46) was

prepared by the cyclization reaction of 3-amino-5-benzylthio-2H-1,2,4-

triazole with diethyl malonate in sodium methoxide (35)

.

Cyclization of 3-amino-2-(cyanoethyl)-5-substituted-1,2,4-triazoles

(47a-c) by refluxing in toluene for 48 hours afforded 5-amino-1,2,4-triazolo-

[1,5-a]pyrimidine derivatives (48a-c) (36)

.


16

Toluene

refluxN

N NH2N

N

NR

CH2CH2CN

NH2

N

N

R

47a-c 48a-c

N

N

H3C NH

NH2

Ar

NaNO2 / AcOH

CH2Cl2

N

N

H3C

Ar

N

N

N

F3C F3C

Ar = MeO

OMe

Br

49 50

1.2. From pyrimidine derivatives:

Triazolo[4,5-d]pyrimidine derivative (50) was achieved by the

diazotization of the pyrimidine derivative (49) with sodium nitrite and

acetic acid in methylene chloride (37)

.

The reaction of 4-hydrazinopyrimidine derivatives (51a-c) with

trimethylorthoformate in THF afforded the triazolo[4,3-c]pyrimidine

derivatives (52a-c) as novel Syk inhibitors (38)

.

R

a CH3

b C2H5

c Ph


17

N

N

HN

NC

NHNH2

NH

Ar

N

N

HN

NC

NH

Ar

NN

Ar'Ar'

CH (OMe)3

51a-c 52a-c

Ar =

MeO

MeO

NMeS

NC

NH2

CH3

CH3

O

CH(OEt)3

Ac2O

NMeS

NC

N

CH3

CH3

O

HC OEt

Ar NH2

CH3CN

NMeS

NC

CH3

NN

CH2

Ar

53

54a-d

2. Synthesis of pyridopyrimidines:

2.1. From pyridine derivatives:

Pyrido[4,3-d]pyrimidine derivative (54a-d) was produced by the reaction

of 4-aminopyrimidine derivative (53) with triethyl orthoformate using

acetic anhydride as catalyst followed by treatment with different amines in

acetonitrile (39)

.

Ar’

a CH2CH2OTBS

b CH2CO2But

c CH2CH2NHBoc

Ar

a C6H5CH2

b 2-F-C6H4CH2

c 4-F-C6H4CH2

d 4-F-C6H4CH2CH2


18

O

Ar

CH2

NH

Me

MeCl

+

N

R

EtOH

HCl

N

N

H

Ar

O

R

Cl

NH2

56 55

57a-c

HN

NH

O

S N Ph

C CEtOOC COOEt HN

NH

O

S N

COOEt

COOEt

Ph

58 59

Condensation of 2-aminopyridines (56) with enone Mannich bases (55)

in ethanol and the presence of hydrochloric acid afforded pyrido[1,2-a]-

pyrimidines (57a-c) (40)

.


Cycloaddition reaction of azadiene (58) with diethyl acetylene-

dicarboxylate yielded pyrido[2,3-d]pyrimidine derivative (59) (41)

.

5-Aryl-5,11-dihydro-1H-indeno[2’,1’:5,6]pyrido[2,3-d]pyrimidine-2,4,6-

triones (60a-e) were prepared by Hantzsch cyclization of indan-1,3-dione

with aromatic aldehyde and 6-aminouracil in acetic acid (42)

.

R Ar

a H 4-Br-C6H4

b 3-Me C6H5

c 6-Me C6H5CH2O


19

O

O

+ Ar CHO +NH

HNH2N

O

O

AcOH

HN

NH

HN

O Ar

O

O

60a-e

N NH

NH2R

+

O

O

CH3

Ph

O

NN

N

R

Ph

CH3

O OH

MW

61a-d

62a-d

3. Synthesis of pyrazolopyrimidines:

3.1. From pyrazole derivatives:

6-(2-Hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines

(62a-d) were achieved by regioselective microwave-assisted reaction of

5-aminopyrazole derivatives (61a-d) with 3-benzoyl-2-methyl-4H-chromen-

4-one (43)

.

Ar

a C6H5

b 3-F3C-C6H4

c 3-Br-C6H4

d 3-CN-C6H4

e 3-F-C6H4

Ar

a CH3

b But

c 4-Br-C6H4

d 4-NO2-C6H4


21

N

HN

H2N

EtOOC

O

Me2N

+ AcOH N

N

N

COOEt

NO2

NO2

Fe/ AcOH

N

N

N

COOEt

NH2

Ar COCl

PyridineN

N

N

COOEt

HN

COAr

63

F3C

Ar =

64

N

NH

O

O

H3C

NH

NH2

+N

C

O

Ph

EtOHN

NH

O

O

H3C

NH

N

NHPh

65 66

The B-Raf kinase inhibitor pyrazolo[1,5-a]pyrimidine-3-carboxylate

derivative (64) was synthesized from the reaction of 5-amino-1H-pyrazole-

4-carboxylate with compound (63) in acetic acid followed by reduction and

aroylation (44)

.


6-Hydrazinouracil (65) was reacted with phenylisocyanate at room

temperature then refluxed in ethanol to furnish the corresponding

pyrazolo[3,4-d]pyrimidine (66) (45)

.


21

O

N

NH2

R +

O

COOEt

Xylene

O

N

RN O

O

N

RN

O

+

67a-c

68a-c 69a-c

N

ONH2

CN

CH (OEt)3

N

ON

CN

CH

OEt

N

ON

N

NH

RN

ON

N

NHR

Base

RNH2

71a-d 72a-d

70

4. Synthesis of oxazolopyrimidines:

4.1. From oxazole derivatives:

2-Amino-5-substituted-2-oxazolines (67a-c) were refluxed with ethyl

2-oxocyclopentane carboxylate in xylene to afford a mixture of isomeric

oxazolo[3,2-a]pyrimidines (68a-c) and (69a-c) (46)

.

Reaction of 5-aminooxazole-4-carbonitrile with triethyl orthoformate

gave an ethoxymethyleneamino derivative (70) which cyclized with the

appropriate amine to the isolable 7-iminooxazolo[5,4-d]pyrimidine

derivatives (71a-d). However, the latter underwent a Dimorth rearrangement

under basic conditions to7-amino derivatives (72a-d) (47)

R

a C6H5O

b Piperidinyl

c 4-Et-C6H4O

R

a Me

b Et

c Prn

d PhCH2


22

N

N

O

O

R

N3

R1

+PPA

N

N

O

O

R

R1

N

O

PhPh COOH

74 73

N

N

O

O

R

O

R1

+ N

Cl

Cl

CH3

CH3

Cl

CHCl3N

N

O

O

R

O

R1

Cl

NMe2

N

N

O

O

R

O

R1

N3

NMe2

(CH3)3SiN3

N

N

O

O

R

R1

O

N

NMe2

reflux

rt

75

76 77


Oxazolo[5,4-d]pyrimidine-5,7-diones (74) were produced by thermolytic

reaction between 6-azidouracils (73) and benzoic acid in the presence of

PPA (48)

.

Condensation of 1,3-disubstitutedbarbituric acid (75) with dimethyl-

dichloromethyleniminium chloride and subsequent treatment with trimethyl-

silylazide afforded (77) through the rearrangement of the highly unstable

α-azidoenamines (76) (49)

.


23

N

SS

N

CO2Et

CPh N Ph

+ R NH2N

SS

N

CO2Et

CPhNHPh

NHR

EtONa

EtOH

N

S

S

Ph

N

N

Ph

O

NHR

78

79a-e

N

SNH2

+OR'

R

acetone N

SN R'

R

80a-d

5. Synthesis of thiazolopyrimidines:

5.1. From thiazole derivatives:

Thiazolo[4,5-d]pyrimidines (79a-e) were obtained by the reaction of

thiazole carbodiimide derivative (78) with different amines followed by

cyclization in sodium ethoxide and ethanol (50)

.

The reaction of 2-aminothiazoline with α,β-unsaturated carbonyl

compounds under mild conditions yielded dihydrothiazolo[2,3-a]pyrimidines

(80a-d) (51)

.

R

a 3-MeBn

b 2-FBn

c 4-FBn

d Bui

e But

R R’

a Me H

b Ph Me

c Ph Et

d Ph Ph


24

HN

NH

O

SCN

NH2O

DMFHN

NH

O

O N

S

NH2

81

NH

NH

Ar

MeO2C

H3C S

+ ClCH2COOH +

R

CHO

AcOH / Ac2O

N

N

Ar

MeO2C

H3C S

O

CH

R

NaOAc82

83a-d

F

Ar =


Preparation of 2-aminothiazolo[4,5-d]pyrimidine-5,7-dione (81) was

achieved via thermal cyclization of 4-aminouracil-5-thiocyanate in DMF (52)

.

Three-component reaction of pyrimidine derivative (82), chloroacetic

acid and aromatic aldehyde produced thiazolo[3,2-a]pyrimidines (83a-d) (53)

.

R

a H

b 4-Me

c 4-MeO

d 4-Cl


25

N

N

OH

OH

HNO3 / AcOH

N

N

OH

OH

NO2

20o c

84

REACTIONS OF PYRIMIDINES

1) Electrophilic substitution:

Formal replacement of a CH unit in pyridine by a nitrogen atom reduces

the capacity of corresponding diazine towards electrophilic substitution.

Electrophilic substitution is difficult in simple inactivated diazine because of

both extensive protonation under strongly acidic conditions and the inherent

lack of reactivity of the free base. For these reasons, one strongly electron-

releasing group, at least, must be present to make the reaction successful.

a) Nitration:

Pyrimidines normally require the presence of at least two electron-

releasing groups for successful nitration. Thus, 4,6-dihydroxypyrimidine was

nitrated using nitric acid in acetic acid at 20c to give the 5-nitroderivative

(84) (54)

.

b) Sulphonation:

Contrary to nitration, sulphonation needs only one electron releasing

group and takes place at position 5. Sulphonation of 2-aminopyrimidine using

fuming sulphuric acid at 180c gave 2-amino-5-sulphopyrimidine (85) (55)

,

while chlorosulphonation of 2,4-dihydroxypyrimidine at 110c gave

5-(chlorosulphonyl)-2,4-dihydroxypyrimidine (86) which reacted with sodium

carbonate to give 2,4-dihydroxy-5-sulphopyrimidine (87) (56)

.


26

N

N

NH2

H2SO4

180oc

N

N

NH2

SO3H

85

N

N

OH

OH

ClSO3H

110oc

N

N

OH

OH

SO2Cl

Na2CO3

N

N

OH

OH

SO3H

86 87

N

H

N

NH2

O

Br2 / AcOH

N

H

N

NH2

O

Br

88 89

N

H

NH

O

O

F2 / H2SiF2

N

H

NH

O

O

F

90

c) Halogenation:

Typically, pyrimidines having at least one electron-releasing substituent

may be halogenated at position 5 by chorine or bromine in aqueous solution

or by bromine in acetic acid. N-chlorosuccinimide, N-bromosuccinimide,

phosphoryl chloride, phosphoryl bromide and phosphorous pentachloride

have been used for the 5-halogenation of some pyrimidines.

The reaction of cytosine (88) with bromine in acetic acid provided

5-bromocytosine (89) as a major product (57)

.

5-Fluorouracil (90) was prepared by the interaction of uracil with

fluorine in 40% H2SiF2 at 70c (58)

.


27

N

N

CH3

SH CH3

+

+N2

SO2NH2 N

N

CH3

SH CH3

NN

SO2NH2

91 92

N

H

N

O

MeS Ph

CN

PhNH2

N

H

N

O

PhHN Ph

CN

93 94

N

NH

O O

Cl

CH3

RNHNH2

N

NH

O O

NRNH2

CH3

95 96a-c

d) Diazo-Coupling:

Pyrimidines may be coupled with diazotized amines to give 5-arylazo-

derivatives. Thus, treatment of 4,6-dimethyl-2-mercaptopyrimidine (91) with

diazotized p-aminobenzenesulphonamide leads to the formation of 4,6-

dimethyl-5-(sulphamylbenzeneazo)-2-mercaptopyrimidine (92) (59)

.

2) Nucleophilic substitution:

a) Reaction with amines and hydrazines:

5-Cyano-2-methylthio-6-phenylpyrimidine-4-one (93) was reacted with

aniline to give 5-cyano-2-(phenylamino)-6-phenylpyrimidine-4-one (94) (60)

.

6-Chloro-3-methyluracil (95) was reacted with hydrazine, methyl-

hydrazine and benzylhydrazine to give the corresponding hydrazino-


.

R

a H

b Me

c Bn


28

N

N

Cl

ClH3C

NaOH N

N

OH

ClH3C

97

N

NSH3C

O

O KCNN

NNC

98 99

N

NH

Ar

NC

SMe

S

+ BrCH2COOEtK2CO3

N

N

Ar SMe

SEtO2C

H2N

100a-c 101a-c

b) Hydrolysis:

The reaction of 4,6-dichloro-2-methylpyrimidine with sodium hydroxide

provided 4-chloro-6-hydroxy-2-methylpyrimidine (97) (62)

.

c) Cyanation:

Treatment of 2-pyrimidinyl-methylsulfone (98) with potassium cyanide

afforded 2-cyanopyimidine (99) (63)

.

3) Alkylation and acylation:

2-Methylthio-4-thioxopyrimidines (100a-c) were treated with ethyl

bromoacetate and potassium carbonate in ethanol to give thieno[2,3-d]-


.

Ar

a C6H5

b 4-MeO-C6H4

c 4-Cl-C6H4


29

N

N

NH2

OCH3H3C

(ClCH2CO)2O N

N

NHCOCH2Cl

OCH3H3C

102

103

104

105

2-Chloroacetamido-4-methoxy-6-methylpyrimidine (102) was obtained

by acylation of 2-amino-4-methoxy-6-methylpyrimidine with (ClCH2CO)2O

in dioxane (65)

.

4) Reaction with active methylene group containing compounds:

2-Aminopyrimidine was reacted with ethyl 2-chloroacetoacetate

and furnished ethyl imidazo[1,2-a]pyrimidine-5-carboxylate (103) which

was converted into the corresponding carboxylic acid (104) by alkaline

hydrolysis (66)

.

Reaction of 4-amino-5-phenylpyrimidine with diethyl phenylmalonate

gave pyrimido[1,6-a]pyrimidine derivative (105) (67)

.

N

N

NH2

+ CH3COCH(Cl)COOEt

N

N

N

CH3

COOEt

N

N

N

CH3

COOH

-OH

N N

NH2

Ph

+ PhCH(COOEt)2

N N

Ph

N O

Ph


31

106

107 108

BIOLOGICAL ACTIVITY OF PYRIMIDINE DERIVATIVES

Condensed and non-condensed pyrimidines are biologically interesting

molecules that have established utility in the pharmaceutical and the

agrochemical industries. Compounds with these ring systems have diverse

pharmacological activity such as anticancer (68)

, anti-inflammatory (69,70)

,

antitumor (17,71)

, antibacterial (72-74)

, antimalarial (75)

and antifungal (76)

.

A number of substituted quinolinyl pyrimidines (106) were synthesized

as a new class of anti-infective agents and showed a good antitubercular and

antimalarial activities (77)

.

A series of novel 2,4,5-trisubstituted pyrimidine derivatives (107and

108) were evaluated for inhibition against the human hepatocellular

carcinoma BEL-7402 cancer cell line and several compounds showed potent

inhibition with an IC50 value less than 0.10 µM (78)

.

NCl

O

N

N

R

NH2

N

N

CH3

R2

OH

N

N

NH2

R2

OH


31

109

110

N-Benzyl-2-[2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl]-

acetamide (109) can be used as inhibitor of human hydroxysteroid

dehydrogenase (HSD) (79)

.

Pharmacological studies of some substituted 1H-pyrazolylthiazolo[4,5-d]-

pyrimidines (110) showed that they possess anti-inflammatory and

antimicrobial activities (80)

.

2-(2-Aroylaroxy)-4,6-dimethoxypyrimidines (111) were screened for

their anti-inflammatory activity and have shown superior anti-inflammatory

activity in the range 21.5-48.6 % . Compounds with chloro and fluoro groups

at para position in benzoyl and phenoxy moieties of benzophenone elicited

maximum inhibition (48.6 %) (81)

.

MeO

N

H

N

O

O

NH

NH

N

S

N

O

N

N

R

NN CH3


32

111

112 113

114 115

A new series of 2,4,6-trisubstituted pyrimidine derivatives (112, 113,

114 and 115) showed an excellent activity against leishmania (82)

.

N

N

OCH3

OCH3OO

R1

R2

OCH3

H3CO

H3CO

NN

NH2

N

OCH3

H3CO

H3CO

NN

NH2

N

O

OCH3

H3CO

H3CO

NN

NH2

N

NEt

OCH3

H3CO

H3CO

NN

NH2

NH

CH3

CH3

CH3

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